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Preview: Chirality


Wiley Online Library : Chirality

Published: 2017-12-01T00:00:00-05:00


A chiral enantioseparation generic strategy for anti-Alzheimer and antifungal drugs by short end injection capillary electrophoresis using an experimental design approach


The present study describes a generic strategy using capillary electrophoretic (CE) method for chiral enantioseparation of anti-Alzheimer drugs, namely, donepezil (DON), rivastigmine (RIV), and antifungal drugs, namely, ketoconazole (KET), Itraconazole (ITR), fluconazole (FLU), and sertaconazole (SRT) in which these drugs have different basic and acidic properties. Several modified cyclodextrins (CDs) were applied for enantioseparation of racemates such as highly sulfated α, γ CDs, hydroxyl propyl-β-CD, and Sulfobutyl ether-β-CD. The starting screening conditions consist of 50-mM phosphate-triethanolamine buffer at pH 2.5, an applied voltage of 15 kV, and a temperature of 25°C. The CE strategy implemented in the separation starts by screening prior to the optimization stage in which an experimental design is applied. The design of experiment (DOE) was based on a full factorial design of the crucial two factors (pH and %CD) at three levels, to make a total of nine (32) experiments with high, intermediate, and low values for both factors. Evaluation of the proposed strategy pointed out that best resolution was obtained at pH 2.5 for five racemates using low percentages of HS-γ-CD, while SBE-β-CD was the most successful chiral selector offering acceptable resolution for all the six racemates, with the best separation at low pH values and at higher %CD within 10-min runtime. Regression study showed that the linear model shows a significant lack of fit for all chiral selectors, anticipating that higher orders of the factors are most likely to be present in the equation with possible interactions.

Biomimetic syntheses of racemic natural products


Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors. Biomimetic synthesis of these racemic natural products provides support for their proposed nonenzymatic spontaneous biosynthesis. These elegant syntheses also provide scalable and efficient routes to these complex natural products. Although the number of reported racemic natural products is relatively low, an isolated natural product that has a very small optical rotation has been shown to be a true racemate. Thus, the occurrence of racemic natural products could be more common than thought.

An oxorhenium complex bearing a chiral cyclohexane-1-olato-2-thiolato ligand: Synthesis, stereochemistry, and theoretical study of parity violation vibrational frequency shifts


In our effort towards measuring the parity violation energy difference between two enantiomers, a simple chiral oxorhenium complex 5 bearing enantiopure 2-mercaptocyclohexan-1-ol has been prepared as a potential candidate species. Vibrational circular dichroism revealed a chiral environment surrounding the rhenium atom, even though the rhenium is not a stereogenic center itself, and enabled to assign the (1S,2S)-(−) and (1R,2R)-(+) absolute configuration for 5. For both compound 5 and complex 4, previously studied by us and bearing a propane-2-olato-3-thiolato ligand, relativistic calculations predict parity violating vibrational frequency differences of a few hundreds of millihertz, above the expected sensitivity attainable by a molecular beam Ramsey interferometer that we are constructing.

Lipase-catalyzed enantioselective transesterification of prochiral 1-((1,3-dihydroxypropan-2-yloxy)methyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione in ionic liquids


The application of ionic liquids as solvents for transesterification of prochiral pirymidine acyclonucleoside using lipase (EC Amano PS from Burkholderia cepacia (BCL) is reported. The effect of using medium reaction, acyl group donor, and temperature on the activity and enantioselectivity of BCL was studied. From the investigated ionic solvents, the hydrophobic ionic liquid [BMIM]PF6] was the preferred medium for enzymatic reactions. However, the best result was obtained in the mixture [BMIM][PF6]:TBME (1:1 v/v) at 50°C. Enzyme activity and selectivity in [BMIM][PF6]:TBME (1:1 v/v) was slightly higher in than in conventional organic solvents (for example, TBME), and in this condition, good activity and enantioselectivity were associated with unique properties of ionic liquid such as hydrophobicity and high polarity. Independently of solvents, monester of (R)-configuration was obtained in excess. Under optimal conditions, desymmetrization of the prochiral compound using different acyl donors was performed. If vinyl butyrate was used as the acylating agent, BCL completely selectively acylated enantiotopic hydroxyl groups.

Di(1-naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination


The absolute stereochemistry of chiral carboxylic acids is determined as a di(1-naphthyl)methanol ester derivative. Computational scoring of conformations favoring either P or M helicity of the naphthyl groups, capable of exciton-coupled circular dichroic coupling, leads to a predicted stereochemistry for the derivatized carboxylic acids.

Production of (R)-1-(1,3-benzodioxol-5-yl)ethanol in high enantiomeric purity by Lactobacillus paracasei BD101


Piperonyl ring is found in a number of naturally occurring compounds and possesses enormous biological activities. There are many studies in the literature with compounds containing a piperonyl ring, but there are very few studies on the synthesis of chiral piperonyl carbinol. The objective of this study was to determine the microbial reduction ability of bacterial strains and to reveal the effects of different physicochemical parameters on this reduction ability. A total of 15 bacterial isolates were screened for their ability to reduce 1-(benzo[d][1,3]dioxol-5-yl) ethanone 1 to its corresponding alcohol. Among these isolates Lactobacillus paracasei BD101 was found to be the most successful biocatalyst to reduce the ketone containing piperonyl ring to the corresponding alcohol. The reaction conditions were systematically optimized for the reducing agent L paracasei BD101, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale study was performed, and a total of 3.72 g of (R)-1-(1,3-benzodioxol-5-yl) ethanol in high enantiomeric form (>99% enantiomeric excess) was produced in a mild, cheap, and environment-friendly process. This study demonstrates that L paracasei BD101 can be used as a biocatalyst to obtain chiral carbinol with excellent yield and selectivity.

Hemin and bile pigments are the secondary structure regulators of intrinsically disordered antimicrobial peptides


The interaction of protoporphyrin compounds of human origin with the major bee venom component melittin (26 a.a., Z +6) and its hybrid derivative (CM15, 15 a.a., Z +6) were studied by a combination of various spectroscopic methods. Throughout a two-state, concentration-dependent process, hemin and its metabolites (biliverdin, bilirubin, bilirubin ditaurate) increase the parallel β-sheet content of the natively unfolded melittin, suggesting the oligomerization of the peptide chains. In contrast, α-helix promoting effect was observed with the also disordered but more cationic CM15. According to fluorescence quenching experiments, the sole Trp residue of melittin is the key player during the binding, in the vicinity of which the first pigment molecule is accommodated presumably making indole-porphyrin π-π stacking interaction. As circular dichroism titration data suggest, cooperative association of additional ligands subsequently occurs, resulting in multimeric complexes with an apparent dissociation constant ranged from 20 to 65 μM. Spectroscopic measurements conducted with the bilirubin catabolite urobilin and stercobilin refer to the requirement of intact dipyrrinone moieties for inducing secondary structure transformations. The binding topography of porphyrin rings on a model parallel β-sheet motif was evaluated by absorption spectroscopy and computational modeling showing a slipped-cofacial binding mode responsible for the red shift and hypochromism of the Soret band. Our results may aid to recognize porphyrin-responsive binding motifs of biologically relevant, intrinsically disordered peptides and proteins, where transient conformations play a vital role in their functions.

Electronic and vibrational exciton coupling in oxidized trianglimines


Readily available chiral trianglimine and their (poly)oxygenated congeners represent a unique class of macrocyclic rigid compounds optimal for testing electronic and vibrational circular dichroism exciton chirality methods. Electronic and vibrational circular dichroism spectra of such trianglimines are strongly affected by polar substituents in macrocycle skeletons. Double substitution by OH groups in each aromatic fragment of the macrocycle causes sign reversal of the exciton couplet in the region of the strongest UV absorption. On the other hand, electronic circular dichroism spectrum of the macrocycle having 2 methoxy groups shows 2 exciton couplets—the long-wavelength positive and the second of the negative sign, observed at the shorter wavelengths. VCD spectra of macrocyclic imines show vibrational exciton couplets in the region of strong C=N stretches. The signs of these couplets are positive and the opposite of the diamine chirality. For trianglimine macrocycles the interpretation of VCD spectra in terms of excitons is much more convincing than for electronic circular dichroism spectra. By contrast, trans-1,2-diaminocyclohexane–based vicinal diimines, being a one-third of the respective macrocycle, do not exhibit any vibrational exciton effect. Experimental data were confronted with DFT calculations. We observed good-to-excellent agreement between experimental and computed data.

Absolute configuration of the diterpenoids icetexone and conacytone from Salvia ballotaeflora


Detailed literature inspections regarding the diterpenoids icetexone (1) and conacytone (3) reveal that the absolute configuration (AC) of these natural occurring compounds is not rigorously proven, despite they were originally isolated in 1976. This task is now completed by single-crystal X-ray diffraction Flack and Hooft parameters determination after processing data collected with Cu Kα graphite monochromated radiation. The AC of both compounds is further determined by vibrational circular dichroism measurements performed on icetexone acetate (2) and conacytone triacetate (4) since the solubility of 1 and 3 is limited. Comparison of the substituent chemical shifts (SCS) induced by acetylation of 1 and 3 to afford 2 and 4, respectively, reveals that in the case of icetexone, all six SCS values of the quinone ring are in excellent agreement with the expected values, while in the case of conacytone, three agree and three do not agree due to the presence of additional acetates near the quinone ring. Density functional theory calculations performed on 3-hydroxythymoquinone (6) and its tautomer 4-hydroxy-1,2-quinone 7, on 6-hydroxythymoquinone (8) and its tautomer ortho-quinone 9, and on icetexone (1) and the claimed natural occurring ortho-quinone tautomer romulogarzone (5) indicate that 2-hydroxy-1,4-quinones are more stable, by some 11-14 kcal/mol, than their 4-hydroxy-1,2-quinone tautomers, and therefore, romulogarzone (5) is inexistent.

Stereochemical analysis of β-keto sulfoxides by circular dichroism


Three β-keto sulfoxides (1–3) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2, the X-ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β-keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.

A stereodynamic fluorescent probe for amino acids. Circular dichroism and circularly polarized luminescence analysis


The use of stereodynamic probes is becoming one of the leading strategies for the fast and effective determination of enantiomeric excess. Recently, we reported a series of novel molecular architectures based on a modified tris(2-pyridylmethyl)amine complex (TPMA), which are able to amplify the electronic CD, in the case of Zn(II) assemblies and vibrational CD, in the case of Co(II) assemblies. Herein, we report a structural modification of the ligand with the purpose to obtain a fluorescent chiral probe. The study deals with the synthesis of the novel ligand, the formation of the self-assembly system with amino acids, and the study of the electronic CD and circularly polarized luminescence.

Exploring potentialities and limitations of stapled o-oligo(phenyleneethynylene)s (o-OPEs) as efficient circularly polarized luminescence emitters


In this paper, we have studied the chiroptical properties of a family of o-oligo(phenyleneethynylene) (o-OPE) derivatives with different steric hindrance. Experimental results show high dissymmetry factors (gabs and glum up to 1.1 × 10−2) and very similar electronic circular dichroism (ECD) and circularly polarized luminescence (CPL) for all the derivatives that make this basic o-OPE scaffold a robust pure organic emitter. Vibrational circular dichroism spectra are used to characterize conformational properties in solution. Density functional theory and time-dependent density functional theory calculations support experimental results also proving that ECD and CPL are almost exclusively linked to helical moiety and not to size or conformation of substituents. As chiroptical properties of these emitters are independent of substituents, this OPE scaffold can be used as basic skeleton for the design of sensing probes with high CPL efficiencies.

Transition dipole coupling modeling of optical activity enhancements in macromolecular protein systems


Optical activity of regular molecular assemblies, such as protein fibrils or nucleic acid condensates, is often significantly stronger than for isolated molecules. Previous modeling suggested that this may be caused by the ordered quasi-periodic structure and a long-order synchronization of chromophore excitations. In the present study, we briefly review this phenomenon and investigate some aspects on simple models related to protein vibrational optical activity. The transition dipole coupling (TDC) model is used to generate vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectra. While a linear arrangement of chromophores produced relatively simple couplet intensity patterns, a richer band structure was predicted for planar geometries. A stacking of β-sheet planes has been identified as another powerful source of the enhancement. The results do not completely reproduce experimental observations but are consistent with them and confirm that chiroptical methods may be extremely useful to study aggregation of chiral molecules. The transition dipole coupling model allows to vary systematically many parameters, such as chromophore geometries and transition dipoles. We used it to explore conditions favorable to chirality enhancement observed in many experiments on protein amyloidal precipitates. Stacking of β-sheet planes has been identified as a particularly powerful mechanism of the enhancement.

Convenient enzymatic resolution of (R,S)-2-methylbutyric acid catalyzed by immobilized lipases


The application of several immobilized lipases has been explored in the enantioselective esterification of (R,S)-2-methylbutyric acid, an insect pheromone precursor. With the use of Candida antarctica B, using hexane as solvent, (R)-pentyl 2-methylbutyrate was prepared in 2 h with c 40%, eep 90%, and E = 35, while Thermomyces lanuginosus leads to c 18%, eep 91%, and E = 26. The (S)-enantiomer was obtained by the use of Candida rugosa or Rhizopus oryzae (2-h reaction, c 34% and 35%, eep 75 and 49%, and E = 10 and 4, respectively). Under optimal conditions, the effect of the solvent, the molar ratio, and the nucleophile were evaluated.

On the aggregation of bilirubinoids in solution as evidenced by VCD and ECD spectroscopy and DFT calculations


Vibrational and electronic circular dichroism (VCD and ECD) spectra of 3 optically active bilirubin analogs with propionic acid groups replaced by (1) 1-(S)-methylpropyl groups, (2) 3-acetoxy-1-(S)-methylpropyl groups, and (3) 1-(S)-2-(R)-dimethyl-2-(methoxycarbonyl)ethyl groups have been recorded at different concentrations in chloroform. The aliphatic chains attached to C-8 and C-12 of the 3 chosen mesobilirubins were modified so as to possess no OH group. The variation of the VCD spectra with concentration is consistent with the formation of dimers at high concentration. Density functional theory and time-dependent density functional theory calculations on monomeric and dimeric forms support such a conclusion. Comparing with previous VCD (ECD) and IR (UV) studies of other mesobilirubin molecules, it is concluded that here, the key feature for aggregation is the missing OH groups on the propionic acid chains. The latter, in synergy with the polar groups of lactam moieties, appear to be involved in intramolecular phenomena and thus favor monomeric forms. Investigation of ECD and UV spectra of the same compounds in mixed DMSO/chloroform solutions provide further clues to the proposed picture.

Synthesis of new C3 symmetric amino acid- and aminoalcohol-containing chiral stationary phases and application to HPLC enantioseparations


We recently reported a new C3-symmetric (R)-phenylglycinol N-1,3,5-benzenetricarboxylic acid-derived chiral high-performance liquid chromatography (HPLC) stationary phase (CSP 1) that demonstrated better results as compared to a previously described N-3,5-dintrobenzoyl (DNB) (R)-phenylglycinol-derived CSP. Over a decade ago, (S)-leucinol, (R)-phenylglycine, and (S)-leucine derivatives were used as the starting materials of 3,5-DNB-based Pirkle-type CSPs for chiral separation. In this study, three new C3-symmetric CSPs (CSP 2, 3, and 4) were prepared by combining the ideas and results mentioned above. Here we describe the synthetic procedures and applications of the new C3-symmetric CSPs (CSP 2–CSP 4).

Exploration of the expeditious potential of Pseudomonas fluorescens lipase in the kinetic resolution of racemic intermediates and its validation through molecular docking


A profoundly time-efficient chemoenzymatic method for the synthesis of (S)-3-(4-chlorophenoxy)propan-1,2-diol and (S)-1-chloro-3-(2,5-dichlorophenoxy)propan-2-ol, two important pharmaceutical intermediates, was successfully developed using Pseudomonas fluorescens lipase (PFL). Kinetic resolution was successfully achieved using vinyl acetate as acylating agent, toluene/hexane as solvent, and reaction temperature of 30°C giving high enantioselectivity and conversion. Under optimized condition, PFL demonstrated 50.2% conversion, enantiomeric excess of 95.0%, enantioselectivity (E = 153) in an optimum time of 1 hour and 50.3% conversion, enantiomeric excess of 95.2%, enantioselectivity (E = 161) in an optimum time of 3 hours, for the two racemic alcohols, respectively. Docking of the R- and S-enantiomers of the intermediates demonstrated stronger H-bond interaction between the hydroxyl group of the R-enantiomer and the key binding residues of the catalytic site of the lipase, while the S-enantiomer demonstrated lesser interaction. Thus, docking study complemented the experimental outcome that PFL preferentially acylated the R form of the intermediates. The present study demonstrates a cost-effective and expeditious biocatalytic process that can be applied in the enantiopure synthesis of pharmaceutical intermediates and drugs.

Enantioseparation of racecadotril using polysaccharide-type chiral stationary phases in polar organic mode


Enantioseparation of the antidiarrheal drug, racecadotril, was investigated by liquid chromatography using polysaccharide-type chiral stationary phases in polar organic mode. The enantiodiscrimininating properties of 4 different chiral columns (Chiralpak AD, Chiralcel OD, Chiralpak AS, Chiralcel OJ) with 5 different solvents (methanol, ethanol, 1-propanol, 2-propanol, and acetonitrile) at 5 different temperatures (5–40 °C) were investigated. Apart from Chiralpak AS column the other 3 columns showed significant enantioseparation capabilities. Among the tested mobile phases, alcohol type solvents were superior over acetonitrile, and significant differences in enantioselective performance of the selector were observed depending on the type of alcohol employed. Van't Hoff analysis was used for calculation of thermodynamic parameters which revealed that enantioseparation is mainly enthalpy controlled; however, enthropic control was also observed. Enantiopure standard was used to determine the enantiomer elution order, revealing chiral selector—and mobile-phase dependent reversal of enantiomer elution order. Using the optimized method (Chiralcel OJ stationary phase, thermostated at 10 °C, 100% methanol, flow rate: 0.6 mL/min) baseline separation of racecadotril enantiomers (resolution = 3.00 ± 0.02) was achieved, with the R-enantiomer eluting first. The method was validated according to the ICH guidelines, and its application was tested on capsule and granules containing the racemic mixture of the drug.

Enantiopurity and absolute configuration determination of arene cis-dihydrodiol metabolites and derivatives using chiral boronic acids


The relative merits of the methods employed to determine enantiomeric excess (ee) values and absolute configurations of chiral arene and alkene cis-1,2-diol metabolites, including boronate formation, using racemic or enantiopure (+) and (−)-2-(1-methoxyethyl)phenylboronic acid (MEPBA), are discussed. Further applications of: 1) MEPBA derived boronates of chiral mono- and poly-cyclic arene cis-dihydrodiol, cyclohex-2-en-1-one cis-diol, heteroarene cis/trans-2,3-diol, and catechol metabolites in estimating their ee values, and 2) new chiral phenylboronic acids, 2-[1-methoxy-2,2-dimethylpropyl]phenyl boronic acid (MDPBA) and 2-[1-methoxy-1-phenylmethyl]phenyl boronic acid (MPPBA) and their advantages over MEPBA, as reagents for stereochemical analysis of arene and alkene cis-diol metabolites, are presented.

Cover Image, Volume 29, Issue 12


The cover image, by Deepali B. Magadum and Ganapati D. Yadav, is based on the Regular Article One-pot synthesis of (R)-1-(pyridin-4-yl)ethyl acetate using tandem catalyst prepared by co-immobilization of palladium and lipase on mesoporous foam: Optimization and kinetic modeling, DOI: 10.1002/chir.22743.

Issue Information


No abstract is available for this article.

Sensing site-specific structural characteristics and chirality using vibrational circular dichroism of isotope labeled peptides


Isotope labeling has a long history in chemistry as a tool for probing structure, offering enhanced sensitivity, or enabling site selection with a wide range of spectroscopic tools. Chirality sensitive methods such as electronic circular dichroism are global structural tools and have intrinsically low resolution. Consequently, they are generally insensitive to modifications to enhance site selectivity. The use of isotope labeling to modify vibrational spectra with unique resolvable frequency shifts can provide useful site-specific sensitivity, and these methods have been recently more widely expanded in biopolymer studies. While the spectral shifts resulting from changes in isotopic mass can provide resolution of modes from specific parts of the molecule and can allow detection of local change in structure with perturbation, these shifts alone do not directly indicate structure or chirality. With vibrational circular dichroism (VCD), the shifted bands and their resultant sign patterns can be used to indicate local conformations in labeled biopolymers, particularly if multiple labels are used and if their coupling is theoretically modeled. This mini-review discusses selected examples of the use of labeling specific amides in peptides to develop local structural insight with VCD spectra.

Chiral Molecular Science: How were the absolute configurations of chiral molecules determined? “Experimental results and theories”


Molecular chirality is a key concept in chemistry, bioscience, and molecular technology, like the invention of a light-powered chiral molecular motor explained in this review. Thus, the primary research subject is how to determine the absolute configuration (AC) of chiral compounds. This review article focuses on the principle, theory, and practice of the nonempirical methods for determining ACs of chiral compounds, i.e., the Bijvoet method in X-ray crystallography and the circular dichroism (CD) exciton chirality method, together with the historical aspects of AC determination. The theoretical equations of X-ray crystallography and exciton CD spectroscopy are explained in detail, and these equations are useful for readers to understand the principle and mechanism of these methods. This review also focuses on the relative methods, where the internal reference with known AC is used and the relative configuration is determined by X-ray crystallography and/or 1H nuclear magnetic resonance (NMR) diamagnetic anisotropy method. In these cases, CSDP acid and MαNP acid are useful for the chiral resolution of racemic alcohols, where their diastereomeric esters are easily separable by high-performance liquid chromatography (HPLC) on silica gel. Thus, these methods are useful for the preparation of enantiopure compounds and simultaneous determination of their ACs. In this review article, the above methods are explained mainly based on the author's own research results.

Advances in asymmetric oxidative kinetic resolution of racemic secondary alcohols catalyzed by chiral Mn(III) salen complexes


Enantiomerically pure secondary alcohols are essential compounds in organic synthesis and are used as chiral auxiliaries and synthetic intermediates in the pharmaceutical, agrochemical, and fine chemical industries. One of the attractive and practical approaches to achieving optically pure secondary alcohols is oxidative kinetic resolution of racemic secondary alcohols using chiral Mn(III) salen complexes. In the last decade, several chiral Mn(III) salen complexes have been reported with excellent enantioselectivity and activity in the homogeneous and heterogeneous catalysis of the oxidative kinetic resolution of racemic secondary alcohols. This review article is an overview of the literature on the recent development of chiral Mn(III) salen complexes for oxidative kinetic resolution of racemic secondary alcohols. The catalytic activity of monomeric, dimeric, macrocyclic, polymeric, and silica/resin supported chiral Mn(III) salen complexes is discussed in detail.

One-pot synthesis of (R)-1-(pyridin-4-yl)ethyl acetate using tandem catalyst prepared by co-immobilization of palladium and lipase on mesoporous foam: Optimization and kinetic modeling


The synthesis of (R)-1-(pyridin-4-yl)ethyl acetate was achieved over tandem palladium-lipase catalyst with 100% selectivity using 4-acetyl pyridine as a reactant. The 2% w/w palladium and lipase catalyst was successfully co-immobilized in the microenvironment of the mesocellular foam and characterized by various techniques. The palladium metal from catalyst hydrogenated 4-acetyl pyridine to form 1-(pyridin-4-yl)ethanol. The generated intermediate product then underwent kinetic resolution over lipase and selectively gave (R)-1-(pyridin-4- yl)ethyl acetate. The catalytic conditions were then studied for optimal performance of both steps. The reaction conditions were optimized to 50 °C and toluene as a solvent. Both chemical and enzymatic kinetic models of the reaction were developed for a given set of reaction conditions and kinetic parameters were predicted. At optimal conditions, the obtained selectivity of intermediate (1-(pyridin-4-yl)ethanol) was 51.38%. The final product yield of ((R)-1-(pyridin-4-yl)ethyl acetate) was 48.62%.

Investigation of maltodextrin-based synergistic system with amino acid chiral ionic liquid as additive for enantioseparation in capillary electrophoresis


The combined use of chiral ionic liquids (ILs) and chiral selectors in capillary electrophoresis (CE) to establish a synergistic system has proven to be an effective approach for enantioseparation. In this article, tetramethylammonium-L-arginine, a kind of amino acid chiral IL, was applied to investigate its potential synergistic effect with maltodextrin in CE enantioseparation. The established maltodextrin-based synergistic system showed markedly improved enantioseparations compared with the single maltodextrin system. Parameters such as the chiral IL concentration, maltodextrin concentration, buffer pH, applied voltage, and capillary temperature were optimized. Satisfactory enantioseparation of the five studied drugs, including nefopam, duloxetine, ketoconazole, cetirizine, and citalopram was achieved in 50 mM Tris-H3PO4 buffer solution (pH 3.0) containing 7.0% (m/v) maltodextrin and 60 mM tetramethylammonium-L-arginine. In addition, the chiral configuration of tetramethylammonium-L-arginine was also investigated to demonstrate the existence of a synergistic effect between chiral ILs and maltodextrin. The established maltodextrin-based synergistic system showed marked improved enantioseparations compared with the single maltodextrin system.

Specific optical rotation is a versatile tool for the identification of critical micelle concentration and micellar growth of tartaric acid–based diastereomeric amphiphiles


Four novel tartaric acid–based diastereomeric chiral amphiphiles, two being enantiomers of the other two, have been synthesized and investigated using chiroptical spectroscopic methods, along with tensiometry and dynamic light scattering experiments. We found that an inflection point in specific optical rotation (SOR) values at ~0.32 mM corresponds to the critical micelle concentration (CMC). The increase in magnitude of SOR values beyond CMC corresponds to the growth of aggregates. For enantiomers, oppositely signed SOR values were observed, ruling out the possibility for the presence of aggregation size mediated artefacts. SOR values did not exhibit concentration dependence for a chiral tartaric acid based non-aggregating analogue further establishing the absence of artefacts or anomalous interaction of tartaric acid based head group with solvent. Electronic circular dichroism spectra showed no significant changes in band positions or intensities with concentration. Due to the requirement for higher concentrations (~200 mM) needed to obtain vibrational circular dichroism spectra, these measurements are not found to be useful for studying concentration dependent properties of chiral amphiphiles.

Fast liquid chromatography for racemic atenolol acetate separation—The analytical protocol


Kinetic resolution of (R,S)-atenolol is a faster strategy to produce (S)-atenolol. Since this racemate is a less soluble compound, resolution of its ester offers high concentrations in the process. A good analytical method is required to observe the enantiomer concentrations. This paper described application of ultra-fast liquid chromatography on the atenolol ester separation using different resolution media and analytical procedures. Chiralcel OD column resolved the ester. The chromatograms indicated different characteristics of the process. The enantiomers could be recognized by the column in less than 1 (one) hour. Symmetrical peaks were obtained, but several procedures produced peaks with wide bases and slanted baselines. Efficient enantioresolution was obtained at high mobile phase flow rate, decreased concentration of amine-type modifier, but increased alcohol content in the mobile phase. High UV detection wavelength was required. At 1.0 mL/min, the (90/10/0.5) composition resulted α = 1.46 and RS = 0.9998 that were good separation.

Absolute configuration assignment of (+)-fluralaner using vibrational circular dichroism


The absolute configurations of the separated enantiomers of fluralaner, a racemic animal health product used to prevent fleas and ticks, have been assigned using vibrational circular dichroism (VCD). The crystallographic structure of the active enantiomer (+)-fluralaner has previously been shown to have the (S) configuration using small molecule crystallography. We sought a faster analytical method to determine the absolute configuration of the separated enantiomers. When comparing the measured IR (infrared) and VCD spectra, it is apparent that the amide carbonyl groups appear in the IR but are nearly absent in the VCD. Computational work to calculate the VCD and IR using in vacuo models, implicit solvation, and explicitly solvated complexes has implicated conformational averaging of the carbonyl VCD intensities.